Most of threo-3-amino-2-hydroxybutanoylaminoacetic acids prepared according to this invention are known from U.S. Pat. Nos. 4,029,547 and 4,052,449, British Pat. Nos. 1,510,477 and 1,540,019.
For example, (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoylaminoacetic acid (herein after referred to simply as bestatin) is a least toxic substance isolated from culture filtrates of Streptomyces olivoreticuli as an aminopeptidase B inhibitor (referred to U.S. Pat. No. 4,029,547) by H. Umezawa, et al., which has been found to exhibit an increasing effect to immuno-response such as delayed hypersthesia, activate in vivo defense mechanism and has inhibitive effects for cancer (referred to Japanese Patent Laid-Open Publication No. 117435/1977) and the compound is expected to be useful as a pharmaceutical.
It is also known that several 3-amino-2-hydroxybutanoylaminoacetic acids other than bestatin have equal or more inhibitory activity to aminopeptidase B than bestatin and a synthetic process therefor is disclosed in British Pat. No. 1,510,477. In the process described in the British Patent, however, while (2S,3R)-3-amino-2-hydroxybutanoic acid, for example, as an intermediate for bestatin is synthesized through the steps shown below, the process has various defects as detailed later. ##STR3##
(R)-phenylalanine (1) is converted to a benzyloxycarbonyl derivative (2), which is then condensed with 3,5-dimethylpyrazole by using dicyclohexylcarbodiimide. The 3,5-dimethylpyrazolide (3) is reduced to benzyloxycarbonyl-(R)-phenylalaninal (4) with lithium aluminum hydride, which is then changed to the corresponding adduct (5) by reaction with sodium hydrogen sulfite and further to the cyanohydrin (6) through reaction with a cyanide. The above derivative is hydrolyzed under an acidic condition into (2RS,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid (7), which is again allowed to react with a benzyloxycarbonylating reagent to convert to (2RS,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-butanoic acid (8). The acid is fractionally crystallized into (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (9) by using brucine.
Although the above process can be conducted with no troubles in a laboratory scale, it is not suited to large scale production so that the process includes the use of much expensive (R)-phenylalanine which is not a natural amino acid, the use of highly ignitable lithium aluminum hydride for the reduction of the pyrazolide, as well as the use of a very poisonous cyanide in synthesis of cyanohydrin.
In view of the above, the inventors have made an earnest study seeking for a process suited to mass production with no foregoing defects and, accomplished this invention.
The process according to this invention can produce the end products at a high yield without using an expensive amino acid such as (R)-phenylalanine and with no use of a cyanide, and thus it is much suited to the mass production.